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The impact of electronic data capture on clinical data management

electronic data capture (EDC)-based clinical trials offer operational and cost-effective approaches for ongoing data entry via the Internet for clinical sites; medical monitoring; monitoring by clinical research associates including initial review. Pharmaceutical, biotechnology, and medical device industry, as well as academia and the government, have all begun to adopt EDC as a new data management tool.

The impact of electronic data capture on clinical data management

1.
The Impact of
Electronic Data Capture on
Clinical Data Management
Perspectives from the Present into the Future
Electronic data capture (EDC)-based clinical trials offer operational and
cost-effective approaches for ongoing data entry via the Internet for
clinical sites; medical monitoring; monitoring by clinical research associ-
ates (CRAs), including initial review of data in the home office and then
performing source document veriﬁcation at the study site; identiﬁcation of
potential errors by data management; and determination of the status of
the clinical trial by project management.1-4
Ten years ago, Kelly and Old-
ham5
discussed the challenges of implementing EDC and the potential
advantages in clinical development. Kuchenbecker and colleagues6
foresaw
the emerging role of Internet technologies for data acquisition and pre-
dicted the eventual common use of EDC in the pharmaceutical industry.
Banick7
predicted that with EDC, time to database lock could be reduced by
43% and queries by 86%. The pros and cons of EDC have recently been pre-
sented,8
as well as the challenges for implementing EDC clinical trials.9
Starting a Study
All planning and implementation of EDC must be done prior to enrollment of
the ﬁrst patient. Data entry screens, online edit-check speciﬁcations, and the
annotated case report form (CRF) can, and must be, completed prior to patient
enrollment. Basically, there is no luxury in an EDC trial to put off those tasks,
as can be done with a paper-based CRF trial (often with unintended negative
consequences). Also, there must be upfront and full integration in the design
of the trial with clinical research, data management, and biostatistics to assure
that the data entry process is user-friendly for the clinical sites and that the
exported database structure is compatible with the planned statistical analysis.
Once forms and their associated edit (validation) checks are created, and
assuming that a company adopts and enforces standards, forms and form
elements can easily be reused for other studies through a library system.
With some EDC systems, a new study can be created by merely invoking
the “copy” function, which effectively clones the established system to cre-
ate forms for the next trial (see Figure 1).
In order to initiate a study once the copy function is invoked, one needs
only to add roles, users, and sites, which can also come from the library.
Basically, do this once with agreed-upon standards for forms, variables, and
edit checks, and the EDC study may already be 80% complete once a study
is copied from the library.
With the proper EDC toolbox, which should include a form generator
and programmerless edit checks, the clinical group may now be able to cre-
PEER REVIEWED
Jules T. Mitchel, MBA, PhD | Yong Joong Kim, MS | Joonhyuk Choi, MS
Vadim Tantsyura, MS, MA | Douglas Nadler, MS | Imogene Grimes, PhD
Silvana Cappi, MSc, MBA | Philip T. Lavin, PhD | Kirk Mousley, MSEE, PhD
With the proper EDC
toolbox, . . . the clinical
group may now be able
to . . . deploy a full EDC
study in days rather
than weeks or months.
PEER REVIEWED ❘ 37
TECHNOLOGYINCLINICALRESEARCH

2.
ate the CRF forms and, together with
data management, deploy a full EDC
study in days rather than weeks or
months. The learning curve is not
steep, allowing for paper-competitive
implementation on the ﬁrst EDC study
and accelerated implementation on
subsequent studies. The experience
level of the staff required to perform
the implementation no longer rises to
the level of a software developer or an
EDC expert, although experience is a
plus.
Query Management
Query management has also changed
dramatically, with all outstanding
queries and edit-check resolutions in
an EDC trial being only a click away.
With EDC, the entire query manage-
ment process can be handled within
the website, with no paper queries.
Although queries must still be gener-
ated, they can now be managed via a
web interface, rather than paper forms
in ringbinders. Queries can be resolved
in minutes rather than weeks, assum-
ing that the site is responsive to the
query.
Queries can be resolved
in minutes rather than
weeks, assuming that
the site is responsive to
the query.
Traditionally, batch edit checks, or
“potential queries,” are generated by
data management using statistical
analysis software (SAS) programs or
equivalent software. Then, on a regu-
lar schedule, these edit checks are run
and distributed to either the CRAs or
the data managers for resolution. Once
resolved through the query process or
given an “OK as is” designation, the
edit checks are manually deactivated.
Ongoing through a clinical trial, this
process can be very labor intensive.
With EDC, batch edit checks—
written in SAS, procedural language/
structured query language, or other
software—can be integrated with the
electronic query system of the study.
The EDC system can run the edits and
display the results of those edits
through a discrepancy review screen.
Without having to learn a new pro-
gramming language, traditional SAS
programmers can write the batch edit
checks compatible with an EDC system
that uses SAS directly. The program
code can identify which forms to dis-
play within the query system for each
batch edit check, and supply the ap-
propriate error message. With online
batch edit checks, the ﬁeld monitor is
able to trigger the batch edit checks
and assess them, similar to the man-
agement of a normal range or edit
check generated at the time of data
entry (see Figure 2).
Clinical Trial Oversight
The data manager acts as a bridge
between ﬁeld operations and biostatis-
tics. Although the processes may differ
between companies, the concept is
somewhat universal. Statisticians want
“clean” data, which data management
must deliver. In EDC, there is a dra-
matic drop in the types of data errors
found in paper-based CRF studies, such
as out-of-range values or missing data.
In EDC, there is a
dramatic drop in the
types of data errors
found in paper-based
CRF studies, such as
out-of-range values or
missing data.
Whether the explanation provided
by the site for the condition of the data
is acceptable is another matter, and
that is where the data manager jumps
in. The data manager can view all edit-
check activities and can generate
queries directly to the clinical sites.
This happens in real time; so when it is
time to lock the database, there can be
a very high expectation that the data
are clean. Some data management
tasks, such as providing reports or
notifying the medical monitor about
serious adverse events, may still
require a phone call; these tasks may
38 ❘ MONITOR AUGUST 2008
Figure 1 Copying a Form from the Library

3.
inherently be automated through man-
agement reporting or real-time e-mail
notiﬁcation capabilities.
With the advent of EDC, there is
now an overlap in the ability of the
CRAs, data managers, statisticians, and
project managers to see each other’s
processes and workﬂow. For example,
in a simple management report, the
status of monitoring of the clinical
site’s data entry is available to all:
Data managers, project managers, and
CRAs can all see how many patients
have their data locked and signed elec-
tronically (see Figure 3).
In EDC trials, as CRAs take the time
to review the data prior to the monitor-
ing visit, they can be much more
knowledgeable about the status of
the trial at the time of the monitoring
visit. Issues such as missing data, illog-
ical data, misspellings, and incorrect
terminologies/acronyms can be re-
viewed offsite and then confirmed at
the time of source document review.
The monitor can also have the au-
thorization to prevent the site from
changing data after the monitoring
visit. Of course, all of these tasks can be
reversed at any time prior to database
lock. Data management can also help
the monitor by providing alerts to data
issues as they are entered.
Management reports (or built-in
workflow) can be used to close out a
study, by confirming when all forms
are monitored and locked, and when it
is time for the investigators to sign the
CRF electronically. Once all of these
tasks are accomplished, the study can
be locked. Prior to locking the data for
a patient, a final check ensures that
there are no unresolved edit checks
and queries. When the patient record is
locked, eSignatures can be invoked.
Discussion
With EDC, data entry and data modiﬁ-
cation responsibilities have shifted
from data management to the CRA
and site personnel. This allows data
management personnel to focus on
other “value added” activities. With
EDC, data are entered only once by
those who should know the data the
best (i.e., the clinical study site). The
site coordinator who enters the data
needs to have access to the patient
source records and must be permitted
to make updates to the data per the site
standard operating procedures.
The issue of “who does the entry” at
the site has a large bearing on the suc-
cess of an EDC study. As long as this
task is not “farmed out” to a data entry
clerk who is not familiar with the
patient, there should be only occa-
sional human errors, such as typo-
graphical or transcription errors. The
CRA now assumes some audit func-
tions, and even some of the roles of
data management. In fact, the CRAs
are probably in the best position to
make their job more effective by using
the EDC system for review before mak-
ing site visits. The statisticians are able
to get cleaner data earlier in the pro-
cess, and senior management appreci-
ates the lack of significant delay
between the point of last patient/last
visit and database lock.
However, since EDC represents a
paradigm shift, sponsors must be aware
that training and job descriptions must
be adjusted as workloads are redeﬁned;
in fact, the entire process of data man-
agement must be reconsidered. The
paper-based data management system
does not translate task-by-task into the
EDC system. It is essential to reidentify
the hand-offs and to introduce quality
gates appropriate for the EDC system
where site personnel, monitors, and
data management share responsibilities
for the quality of the data. To the extent
that the EDC application can enforce
workflow, this “new” teamwork be-
comes easier to implement. EDC repre-
sents an opportunity for career
development and for improved job sat-
isfaction through increased team inter-
actions and more control over meeting
timelines.
Since EDC represents a
paradigm shift, sponsors
must be aware that train-
ing and job descriptions
must be adjusted as
workloads are redeﬁned.
When designed properly, EDC can
facilitate data management processes
from CRF generation to monitoring of
the clinical data and integration of edit
checks. The ability to reduce the time
to database lock removes a timeline
PEER REVIEWED ❘ 39
Figure 2 Running SAS Batch Edit Checks within EDC

4.
stress, as statisticians and medical
writers do not need to make up the
delays to database lock.
As EDC prices drop (hopefully) and
scalability improves, the size of the
study should not be a reason why EDC
is used or not used. EDC systems have
now undergone many Food and Drug
Administration audits with no adverse
outcomes delaying or invalidating
approval. Moreover, significant time
and cost savings have evolved from
study start to database lock and final
report by eliminating double-key data
entry; having an integrated query
and online/offline edit-check system;
doing electronic monitoring; and pro-
viding for eSignatures.
Contract research organizations and
sponsors have developed EDC-speciﬁc
processes to implement EDC for every
stage of clinical development in every
therapeutic area. EDC supports stan-
dardization, which can help set up stud-
ies faster. When a single EDC system is
selected for a program, the cloning of
one study to facilitate quick startup of a
similarly structured companion study
will improve efﬁciency of the startup of
later studies. More importantly, it will
facilitate a move toward common stan-
dards for a single program.
Conclusion
The pharmaceutical, biotechnology,
and medical device industry, as well as
academia and the government, have
all begun to adopt EDC as a new data
management tool. EDC acceptance is
strong; there are very few instances
where users have gone back to paper-
based data collection. Though the goal
of data management will not change—
i.e., to assure “clean” data at the end of
the study—there is no doubt that data
management processes will evolve
with the use of EDC systems.
EDC acceptance is
strong; there are very
few instances where
users have gone back
to paper-based data
collection.
When EDC is managed properly,
there is reduced time for study startup,
database cleanup, and database lock,
leaving more time for statistical analy-
ses, ﬁnal study reports, regulatory sub-
missions, and, ultimately, reduced time
to market launch. However, companies
must sort through the multitude of
EDC vendors to identify the software
that is most compatible with their
internal processes and be willing to
restructure and take the appropriate
steps to redo their workﬂow and assure
the appropriate resource allocations.
EDC-enabled data management
process standardization will become a
primary focus for data managers in the
next few years. EDC allows the global-
ization and standardization of data
management operations, and remote
EDC training will become the norm.
The relative importance of database
security will also increase with the
emergence of EDC.
EDC can help clean and lock data
faster than traditional paper CRF sys-
tems. Clinical trial professionals must
adopt new processes, embrace stan-
dardizations, and learn to respond
more quickly to management reports
in addressing issues as they arise. This
will help the clinical data management
department become more effective in
doing its job.
Acknowledgement
The authors would like to thank Joyce
Hays, MS, chief executive officer of
Target Health Inc., for reviewing the
manuscript.
References
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versus web: a tale of three trials. Applied
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Internet-based clinical trials – practical con-
siderations. Pharmaceutical Development and
Regulations 1: 29-39.
3. Mitchel J, You J, Lau A, et al. 2003. Clinical
trial data integrity: using Internet-based
remote data entry to collect reliable data.
Applied Clinical Trials March (Supplement):
6-8.
4. Mitchel J, Jurewicz E, Flynn-Fuchs K, et al.
2005. The role of CRAs in the development
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The Monitor 19(4): 17-21.
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Figure 3 Project Management Report—Data Entry Status

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Jules T. Mitchel, MBA, PhD, is president and
cofounder of Target Health Inc. His more than 25 years of
experience in the pharmaceutical industry includes devel-
opment of drugs, biologics, devices, and diagnostics
involving participation in numerous FDA meetings, prepa-
ration of regulatory submissions, study reports, and prod-
uct development plans. He has held positions at Ayerst
Laboratories (now Wyeth), Pﬁzer Laboratories, and Pﬁzer
Consumer Health Care, and he can be reached at jules
mitchel@targethealth.com.
Yong Joong Kim, MS, is the senior director of
application development and data management at Target
Health Inc. He has the overall responsibility of develop-
ment of the Target eCRF®
and other software products at
Target Health. Previously he worked at the Rockefeller Uni-
versity as an SAS programmer/system analyst for 10 years.
He can be reached at YKim@TargetHealth.com.
Joonhyuk Choi, MS, has served as director of soft-
ware development for Target Health Inc. for the past seven
years. He is one of the lead architects of the Target eCRF®
system and is responsible for developing the company’s
product strategy and architectural direction. He can be
reached at jhchoi@targethealth.com.
Vadim Tantsyura, MS, MA, has 15 years of exten-
sive engineering, information technology, data manage-
ment and project management experience, including eight
years of pharmaceutical experience at Pfizer, Omnicare,
Clinimetrics, Bristol-Myers Squibb, and Regeneron. He is
currently the director of data management at Regeneron
Pharmaceuticals, where he has built the clinical data man-
agement team and led the efforts that culminated in the ﬁrst
Regeneron BLA approval in February of 2008. He can be
reached at vadim.tantsyura@regeneron.com.
Douglas Nadler, MS, is associate director of statis-
tical services at Regeneron Pharmaceuticals, Inc. He has
been in the pharmaceutical/biotech industry for nine years
and can be reached at douglas.nadler@regeneron.com.
Imogene Grimes, PhD, is vice president of data
sciences strategic services at PAREXEL International Cor-
poration. Previously she was vice president, statistics, data
management, and informatics at Regeneron, where she
championed the approval of Regeneron’s ﬁrst BLA. She has
25 years of experience in the pharmaceutical industry,
including a decade in major pharmaceutical companies
(Glaxo and Pﬁzer). She can be reached at imogene.grimes
@parexel.com.
Silvana Cappi, MSc, MBA, is executive director
global biometrics within clinical and nonclinical research
and development at Ferring Pharmaceuticals International
PharmaScience Centre in Copenhagen, Denmark. During
her time as head of the Global Biometrics Department, it
successfully implemented electronic data capture, CDISC
SDTM and ADaM standards, and an outsourcing policy
(with the selection of preferred providers), and Ferring’s
global clinical database, and contributed to the successful
delivery of the company’s first electronic submission
(eCTD). She can be reached at silvana.cappi@ferring.com.
Philip T. Lavin, PhD, is executive chairman, Averion
International Corp. He has served as a faculty member at
the Harvard School of Public Health and Harvard Medical
School and has successfully supported many PMAs, BLAs,
and NDAs with more than 40 direct FDA product approvals.
Over the past 20 years, he has served on multiple FDA
advisory panels. He can be reached at Philip.Lavin@
averionintl.com.
Kirk Mousley, MSEE, PhD, president of Mousley
Consulting, Inc., has directed efforts in computer applica-
tion design and development, clinical database design,
data editing/cleaning, and submissions. His work has
involved numerous database applications, clinical data
management systems, and electronic data capture applica-
tions. He has 20 years of computer systems experience in
the consulting, education, telecommunications, and
aerospace ﬁelds, and he can be reached at kirk@mousley-
consulting.com.
PEER REVIEWED ❘ 41